Estimating the Net Contribution of Interleukin-28B Variation to Spontaneous Hepatitis C Virus Clearance

被引：50

作者：

di Iulio, Julia ^{[1
]}

Ciuffi, Angela ^{[1
]}

Fitzmaurice, Karen ^{[2
,3
]}

Kelleher, Dermot ^{[4
]}

Rotger, Margalida ^{[1
]}

Fellay, Jacques ^{[1
]}

Martinez, Raquel ^{[1
]}

Pulit, Sara ^{[5
]}

Furrer, Hansjakob ^{[6
]}

Guenthard, Huldrych F. ^{[7
,12
]}

Battegay, Manuel ^{[8
]}

Bernasconi, Enos ^{[9
]}

Schmid, Patrick ^{[10
]}

Hirschel, Bernard ^{[11
]}

Barnes, Eleanor ^{[2
,3
]}

Klenerman, Paul ^{[2
,3
]}

Telenti, Amalio ^{[1
]}

Rauch, Andri ^{[6
]}

机构：

[1] Univ Lausanne, Univ Hosp Ctr, Inst Microbiol, CH-1011 Lausanne, Switzerland

[2] Univ Oxford, Oxford Natl Inst Hlth Res, Biomed Res Ctr, Oxford, England

[3] Univ Oxford, Nuffield Dept Clin Med, Oxford, England

[4] Univ Dublin, Inst Mol Med, Dublin, Ireland

[5] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA

[6] Univ Bern, Univ Hosp Bern, Univ Clin Infect Dis, CH-3010 Bern, Switzerland

[7] Univ Zurich, Univ Zurich Hosp, Div Infect Dis, Zurich, Switzerland

[8] Univ Basel Hosp, Dept Med, Infect Dis & Infect Control Clin, CH-4031 Basel, Switzerland

[9] Reg Hosp, Infect Dis Serv, Lugano, Switzerland

[10] Canton Hosp, Div Infect Dis, St Gallen, Switzerland

[11] Univ Hosp Geneva, Div Infect Dis, Geneva, Switzerland

[12] Univ Zurich, Univ Zurich Hosp, Hosp Epidemiol, Zurich, Switzerland

来源：

HEPATOLOGY | 2011年 / 53卷 / 05期

基金：

瑞士国家科学基金会; 英国惠康基金;

关键词：

GENETIC-VARIATION; INFECTION; IL28B; HOST;

D O I：

10.1002/hep.24263

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

The identification of associations between interleukin-28B (IL-28B) variants and the spontaneous clearance of hepatitis C virus (HCV) raises the issues of causality and the net contribution of host genetics to the trait. To estimate more precisely the net effect of IL-28B genetic variation on HCV clearance, we optimized genotyping and compared the host contributions in multiple-and single-source cohorts to control for viral and demographic effects. The analysis included individuals with chronic or spontaneously cleared HCV infections from a multiple-source cohort (n = 389) and a single-source cohort (n = 71). We performed detailed genotyping in the coding region of IL-28B and searched for copy number variations to identify the genetic variant or haplotype carrying the strongest association with viral clearance. This analysis was used to compare the effects of IL-28B variation in the two cohorts. Haplotypes characterized by carriage of the major alleles at IL-28B single-nucleotide polymorphisms (SNPs) were highly overrepresented in individuals with spontaneous clearance versus those with chronic HCV infections (66.1% versus 38.6%, P = 6 x 3 10(-9)). The odds ratios for clearance were 2.1 [95% confidence interval (CI) = 1.6-3.0] and 3.9 (95% CI = 1.5-10.2) in the multiple-and single-source cohorts, respectively. Protective haplotypes were in perfect linkage (r(2) = 1.0) with a nonsynonymous coding variant (rs8103142). Copy number variants were not detected. Conclusion: We identified IL-28B haplotypes highly predictive of spontaneous HCV clearance. The high linkage disequilibrium between IL-28B SNPs indicates that association studies need to be complemented by functional experiments to identify single causal variants. The point estimate for the genetic effect was higher in the single-source cohort, which was used to effectively control for viral diversity, sex, and coinfections and, therefore, offered a precise estimate of the net host genetic contribution. (HEPATOLOGY 2011;53:1446-1454)

引用

页码：1446 / 1454

页数：9

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